With the discovery that the free radical .NO mimics the physiologic property of Endothelium-Derived Relaxing Factor (EDRF) (Furchgott and Zawadzki, Nature, 288: 373-376, 1980; Palmer, et al., Nature, 327: 524-526, 1987), it has become clear that .NO is an essential physiologic factor for maintaining normal life processes. Among the important physiologic functions of .NO is its microbicidal activity when secreted from stimulated macrophages (see, e.g., S. H. Iyengar, et al., Proc. Natl. Acad. Sci. USA, 84: 6369-6373, 1987; Deng, et al., J. Immunol. 151: 322-329, 1993; Weisz, et al., J. Biol. Chem. 269: 8324-8333, 1994; Fang, J. Clin. Invest. 99, 2818-2825; Shiloh, et al., Immunity, 10: 29-38, 1999).
However, the pharmacological applications of .NO are limited, as systemic use can frequently result in severe toxicity. For instance, administration of .NO systemically to treat localized abnormalities or diseases is contraindicated, because the control of its dosage in the therapeutic range cannot be easily achieved. Even if it were possible to carefully titrate the dose of .NO to minimize systemic toxicity, it would be difficult to locally administer this gas to sites of interest. Therefore, the development of therapeutic agents, that mimic the pharmacological action of .NO, has received considerable attention. Several classes of .NO releasing compounds have been developed, including sydnonimine (Noack and Feelisch, J. Cardiovasc. Pharmacol. 14S: 51-55, 1989), nitroglycerin (Noack and Feelisch, J. Cardiovasc. Pharmacol. 14S: 51-55, 1989), S-nitroso derivatives (Ignarro, et al., J. Pharmacol. Exp. Ther. 218: 739-729, 1981; Kowaluk and Fung, J. Pharmacol. Exp. Ther. 255: 1256-1254, 1990; Stamler, Loscalzo, Slivka, Simon, Brown and Drazen, U.S. Pat. No. 5,380,758, 1995) and N-nitroso compounds (Maragos, et al., J. Med. Chem. 34: 3242-3247, 1991; Keefer, Dunams and Saavedra, U.S. Pat. No. 5,366,997; Keefer and Hrabie, U.S. Pat. No. 5,405,919). These compounds require either hydrolysis or metabolic activation, through either oxidation or reduction, to generate NO.. In contrast nitroprusside, a member of a family of organic metallic compounds, can release NO. through light activation (Wolf and Swinheart, Inorg. Chem. 14: 1049-1053, 1975; Bates, et al., Biochem. Pharmacol. 42S: S157-S165, 1991).
Therefore, while the significance of .NO in numerous medical applications is well recognized and while there are numerous methods and compositions known in the art that release .NO, all or almost all of them have various disadvantages. Consequently, there is still a need for compositions and methods in which .NO can be safely and effectively used in the treatment of a disease.